Bone Marrow Transplantation

1. Bone Marrow Transplantation

2. Unlike solid organ transplant, in bone marrow transplantation (BMT) the immunology goes two ways. There is host vs. ​graft disease, but also graft vs. host disease (GVHD) because the marrow graft ​contains functional immune cells. • To undergo BMT the patient first has chemotherapy and radiation to destroy host ​marrow.

3. The human leukocyte antigen (HLA) exists to present antigen to immune cells. • Antigens are ​processed in lysosomes into peptides that are presented in the HLA antigens to T ​lymphocytes. • HLA antigens are the Major Histocompatibility Complexes (MHC). ​

4. The minor histocompatibility antigens are other polymorphic alloantigens that can be ​presented with antigen peptides. • It is easier to match MHC histocompatibility ​between patient and donor than minor histocompatibility antigens.

5. Each HLA antigen is presented with a myriad of peptides, whereas each peptide is ​presented by only a few HLA antigens, so frequency of CTL precursor cells that ​react against an HLA antigen is much higher than CTL precursor cells against ​other alloantigens.

6. HLA antigens are extremely polymorphic but are closely linked on chromosome 6 and ​are inherited as haplotypes (sets of HLAs). Full siblings have ¼ chance of ​inheriting the exact same haplotype set.

7. The most important determinant of GVHD is matching the MHCs. But there are other ​factors. • For example, if there is heavy tissue injury during or just preceding the ​BMT, or if infection occurs during the graft, the cytokines that are released will ​activate host APCs. Host proteins will be seen by the new T lymphocytes in ​conjunction with this co stimulatory signal, increasing the likelihood of GVHD.

8. Temporary immune suppression is normally sufficient, because the new immune cells ​will undergo positive and negative selection against host antigens in the thymus. • ​If there is no thymus, post-thymic donor cells must proliferate to reconstitute the ​immune system, and may include allo reactive lymphocytes.

9. So older patients are ​at much greater risk for GVHD. • More importantly, depletion of T cells from the ​graft helps prevent GVHD, by restricting immune reconstitution to naïve cells. • Depletion of donor T cells helps prevent GVHD, but it slows immune reconstitution, and ​relapse rates are much higher

10. This demonstrates that it’s not just loss of host ​marrow that cures leukemia. The new marrow is actively suppressing the ​leukemia. So if relapse occurs, a simple infusion of donor T lymphocytes induces ​remission. • This is called the graft vs. leukemia effect (GVL). This is a positive ​effect of an allogeneic graft

11. For CML and AML, it is better to have a non-​identical twin donor, because GVL is enhanced by the allogenicity. • The allogenic ​effect is minimal in ALL. • GVHD is associated with a beneficial GVL.

12. T lymphocyte negative selection occurs when the cell’s antigen receptor is stimulated ​without a co stimulatory signal, and the cell undergoes apoptosis. • So, rather than ​just eliminate T cells from a graft, you can prevent GVHD by incubating graft ​marrow with normal patient cells while blocking co stimulatory signals. • The graft ​will develop tolerance to normal host antigens, but retain anti-microbial immunity ​and the graft vs. leukemia effect!